Final outcomes analysis of the cell product SQZ-PBMC-HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration.

Cancer vaccines strive to induce robust, antigen-targeted, T-cell-mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ-PBMC-HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA-A*02+ patients. The SQZ-PBMC-HPV-101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ-PBMC-HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre-dose and post-dose 4 weeks after treatment start. Biomarkers including CD8, MHC-I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre- and post-dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ-PBMC-HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells.

Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A*02+ patients with HPV16+ solid tumors.

We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 - 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 - 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.

Treatment Tolerance of Cetuximab versus Alternative Chemotherapy Agents in Non-Cisplatin Candidates with Head and Neck Cancer Receiving Concurrent Chemoradiotherapy.

INTRODUCTION: Standard of care for radiosensitization in head and neck squamous cell carcinoma (HNSCC) is concurrent chemoradiotherapy (CCRT) with high-dose cisplatin. The optimal chemoradiation regimen for patients medically unfit for cisplatin is unclear. We compared our experience with concurrent cetuximab (CTX) versus other cytotoxic non-cisplatin agents. METHODS: We reviewed 53 patients between 2011 and 2017 with HNSCC treated with CCRT ineligible for cisplatin. Chemotherapy and radiotherapy treatment tolerance was evaluated in those receiving CTX versus non-CTX chemotherapy (NCC). Of the NCC regimens, the majority were carboplatin/paclitaxel and were dosed at an area under the curve (AUC) of 2 and 45-50 mg/m2, respectively. Standard radiation dosing was 70 Gray (Gy) in the definitive setting and 60-66 Gy in the postoperative setting. Patient characteristics and treatment toxicities were evaluated using categorical methods. RESULTS: Patients were well balanced overall including differences between performance status and the comorbidity score. NCC patients experienced more radiation treatment breaks (52.4% vs. 21.9%, p = 0.022), radiation delays >1 week (33.3% vs. 3.1%, p < 0.01), and chemotherapy dose-limiting toxicity (61.9% vs. 28.1%, p = 0.015) compared to CTX patients. Nutritional dependence on a PEG tube was more likely in the NCC cohort (52.4% vs. 22.6%, p = 0.027). CONCLUSION: Our results suggest decreased treatment tolerance in non-cisplatin cytotoxic chemotherapy compared to cetuximab. Further prospective study is needed to clarify optimal chemotherapy in patients unable to receive cisplatin.

A Critical Appraisal and Targeted Intervention of the Oncology Experience in an Internal Medicine Residency.

Most oncology education is provided to residents on an inpatient oncology service, with limited outpatient exposure. There exists considerable need to develop effective education strategies to teach resident physicians basic concepts in oncology. We created a 2-hour small-group interactive workshop, using interactive cases, followed by a number of questions regarding curability, survival, and possible treatment options. All residents were asked to fill out optional questionnaires before and after this workshop. A total of 64 residents participated in this study with an average of 16 residents per session. Significant deficits in knowledge were identified, and prognosis was estimated correctly by 40% of residents when presented with a variety of clinical scenarios. We demonstrated an increase in comfort level in basic oncology concerns, comfort level at estimating prognosis, and managing toxicity based on pre- and post-level testing. Our results confirm that the oncology inpatient rotation may not be adequate in educating residents. The format of our workshop demonstrates that it is possible to create and implement a focused intervention with fairly limited resources. This can serve as a platform for evaluation of oncology medical education of internal medicine residents at other institutions.

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. FUNDING: Merck Sharp & Dohme.

Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: a multicentre, multigroup, phase 2 trial.

BACKGROUND: Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. METHODS: We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m2 on cycle one, day 1, then 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. FINDINGS: Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred. INTERPRETATION: In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. FUNDING: Pfizer.

Impact of Adjuvant Radiotherapy Setting on Quality-of-Life in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: To determine differences in post-treatment QoL across treatment settings in patients receiving adjuvant radiation therapy for head and neck squamous cell carcinoma (HNSCC). METHODS: This was a prospective observational cohort study of patients with HNSCC initially evaluated in a head and neck surgical oncologic and reconstructive clinic at an academic medical center (AMC). Participants were enrolled prior to treatment in a prospective registry collecting demographic, social, and clinical data. Physical and social-emotional QoL (phys-QoL and soc-QoL, respectively) was measured using the University of Washington-QoL questionnaire at pre-treatment and post-treatment visits. RESULTS: A cohort of 177 patients, primarily male and White with an average age of 61.2 ± 11.2 years, met inclusion criteria. Most patients presented with oral cavity tumors (n = 132, 74.6%), had non-HPV-mediated disease (n = 97, 61.8%), and were classified as Stage IVa (n = 72, 42.8%). After controlling for covariates, patients treated at community medical centers (CMCs) reported a 7.15-point lower phys-QoL compared with those treated at AMCs (95% CI: -13.96 to -0.35, p = 0.040) up to 12 months post-treatment. Additionally, patients who were treated at CMCs had a 5.77-point (-11.86-0.31, p = 0.063) lower soc-QoL score compared with those treated at an AMC, which was not statistically significant. CONCLUSION: This study revealed that HNSCC patients treated with radiation at AMCs reported significantly greater phys-QoL in their first-year post-treatment compared to those treated at CMCs, but soc-QoL did not differ significantly. Further observational studies are needed to explore potential factors, including treatment planning and cancer resource engagement, behind disparities between AMCs and CMCs. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3645-3655, 2024.

Prognostic Implications of Skin Invasion in Locally Advanced Oral Cavity Squamous Cell Carcinoma.

OBJECTIVE: To evaluate the effect of histopathologic skin invasion on 2- and 5-year disease-free survival (DFS) and overall survival (OS) in patients treated with primary surgery for locally advanced oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: A retrospective case-control study was performed comparing previously untreated patients with pT4a OCSCC with and without skin invasion. SETTING: Academic medical center. METHODS: Propensity score-matched cohorts were derived by age, sex, surgical margins, pathologic N classification, adjuvant treatment, and primary tumor site. The Kaplan-Meier method was used to evaluate 2- and 5-year OS and DFS, which were compared between cohorts via the log rank (Mantel-Cox) test statistic. RESULTS: Overall 25 patients were identified to have pathologic skin invasion, and 50 were selected for the matched control group. OS was significantly lower for patients with skin invasion as compared with controls at 2 years (30.8% vs 53.3%, P = .018) and 5 years (16.6% vs 42.2%, P = .01). DFS was significantly lower for patients with skin invasion vs controls at 2 years (23.7% vs 47.7, P = .037) and 5 years (15.8% vs 41.4%, P = .024). CONCLUSION: Histopathologic skin invasion in OCSCC is associated with dismal prognosis in patients who underwent primary surgical treatment. OS outcomes for patients with skin invasion are comparable to survival of patients with recurrent/metastatic disease and T4N2 disease.

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study.

PURPOSE: Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS: Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS: The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION: With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Spontaneous Regression of the Pulmonary Metastases in Adenoid Cystic Carcinoma of the Parotid Gland: A Case Report.

Adenoid cystic carcinoma (ACC) is a rare epithelial tumor of the salivary glands with an indolent course and usually bears a long-term survival rate even when metastasized. Spontaneous regression of such a resistant tumor is an even scarce event. We report a case of a patient with ACC of the parotid gland with pulmonary metastases, which spontaneously resolved following resection and post-surgical radiation of the primary tumor. Among the numerous theories proposed to explain such a phenomenon, immunogenic mechanisms and the abscopal effect are the most plausible explanations in this case.

Sarcopenia and Treatment Toxicity in Older Adults Undergoing Chemoradiation for Head and Neck Cancer: Identifying Factors to Predict Frailty.

This study was performed to identify treatment related toxicities in older adults undergoing concurrent chemoradiotherapy for head and neck cancer and nutritional and skeletal muscle measures that might identify frailty. Imaging analysis was done with the following skeletal muscle measurements: skeletal muscle index (SMI), skeletal muscle density (SMD), and skeletal muscle gauge (SMG). Patients were dichotomized by age into younger (<70 years old, 221 patients) and older age groups (≥70 years old, 51 patients). Low SMI was more common in older patients (86.7%) compared to younger patients (51.7%, p < 0.01), as were low SMD (57.8% vs. 37.3%, p = 0.012) and low SMG (76.1% vs. 44.2%, p < 0.01), despite having similar BMIs (27.3 kg/m2 versus 27.7 kg/m2, p = 0.71). Older patients were significantly more likely to experience chemotherapy toxicity than younger patients (54.9% versus 32.3%, p < 0.01). On multivariate analysis age (p < 0.01), current smoking status (p < 0.01), and low SMI (p < 0.01) remained as significant predictors for missed chemotherapy cycles or discontinuation. Older patients were more likely to require ≥5-day radiation breaks than younger patients (27.5% versus 8.6%, p < 0.01). On multivariate analysis, age (p < 0.01), low albumin status (p = 0.03), and low SMI (p = 0.04) were identified as predictors of prolonged radiation treatment breaks. Based on the results of our study, sarcopenia may be used as an additional marker for frailty alongside traditional performance status scales.

A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck.

PURPOSE: Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. PATIENTS AND METHODS: This was a prospective, randomized, double-blind phase II trial of patients with advanced-stage HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy and enrolled between December 2010 and March 2015. Patients received adjuvant everolimus or placebo daily (10 mg, oral) for a maximum of 1 year. p16 IHC as a surrogate marker for human papillomavirus infection and whole-exome sequencing were performed. Cox proportional hazard models estimated hazard rates. Log-rank tests evaluated differences in survival. The primary endpoint was PFS. Secondary endpoints and objectives included overall survival (OS) and toxicity assessment. RESULTS: 52 patients [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] were randomized to placebo (n = 24) or everolimus (n = 28). PFS favored everolimus, but was not significant [log-rank P = 0.093; HR = 0.44; 95% confidence interval (CI), 0.17-1.17]. There was no difference in OS (P = 0.29; HR = 0.57; 95% CI, 0.20-16.2). Everolimus resulted in significant improvement in PFS for p16-negative patients (n = 31; P = 0.031; HR = 0.26; 95% CI, 0.07-0.97), although subgroup analysis showed no difference for p16-positive patients (n = 21; P = 0.93). Further, PFS was significantly higher in TP53-mutated (TP53mut) patients treated with everolimus compared with placebo (log-rank P = 0.027; HR = 0.24; 95% CI, 0.06-0.95). No treatment difference was seen in patients with TP53 wild-type tumors (P = 0.79). CONCLUSIONS: p16-negative and TP53mut patients may benefit from adjuvant treatment with everolimus.

Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048.

OBJECTIVES: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). MATERIALS AND METHODS: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. RESULTS: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. CONCLUSIONS: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.

Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score.

PURPOSE: The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS: Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS: Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION: Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC.

Glomangiomyoma of Uncertain Malignant Potential in the Urinary Bladder: A Case Report.

Glomus tumour typically occurs in subcutaneous tissue but rarely in the visceral organs. Most glomus tumours are benign but few atypical glomus tumours have been reported. Herein, we report a case of a 44-year-old male who presented with hematuria. Transurethral resection of bladder tumour was done. Microscopic examination showed nests and sheets of tumor around the blood vessels. Spindle cells resembling smooth muscle were also observed. An increase in mitosis was observed. These tumour cells show diffuse and strong cytoplasmic positivity for smooth muscle actin and negative for Pancytokeratin, Desmin, Synaptophysin, Chromogranin, S100, and Cluster of Differentiation 34. Ki-67 index was approximately 5%. To our knowledge, this is the first report of Glomangiomyoma of uncertain malignant potential in the urinary bladder which is considered as an unusual variant of atypical glomus tumor. This case emphasizes the importance of broad differential diagnosis which has to be considered in the urinary bladder mass.

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review.

Background: Gut microbiome is proved to affect the activity of immunotherapy in certain tumors. However, little is known if there is universal impact on both the treatment response and adverse effects (AEs) of immune checkpoint inhibitors (ICIs) across multiple solid tumors, and whether such impact can be modulated by common gut microbiome modifiers, such as antibiotics and diet. Methods: A systematic search in PubMed followed by stringent manual review were performed to identify clinical cohort studies that evaluated the relevance of gut microbiome to ICIs (response and/or AEs, 12 studies), or association of antibiotics with ICIs (17 studies), or impact of diet on gut microbiome (16 studies). Only original studies published in English before April 1st, 2020 were used. Qualified studies identified in the reference were also included. Results: At the phylum level, patients who had enriched abundance in Firmicutes and Verrucomicrobia almost universally had better response from ICIs, whereas those who were enriched in Proteobacteria universally presented with unfavorable outcome. Mixed correlations were observed for Bacteroidetes in relating to treatment response. Regarding the AEs, Firmicutes correlated to higher incidence whereas Bacteroidetes were clearly associated with less occurrence. Interestingly, across various solid tumors, majority of the studies suggested a negative association of antibiotic use with clinical response from ICIs, especially within 1-2 month prior to the initiation of ICIs. Finally, we observed a significant correlation of plant-based diet in relating to the enrichment of "ICI-favoring" gut microbiome (P = 0.0476). Conclusions: Gut microbiome may serve as a novel modifiable biomarker for both the treatment response and AEs of ICIs across various solid tumors. Further study is needed to understand the underlying mechanism, minimize the negative impact of antibiotics on ICIs, and gain insight regarding the role of diet so that this important lifestyle factor can be harnessed to improve the therapeutic outcomes of cancer immunotherapy partly through its impact on gut microbiome.

nab-Paclitaxel and cisplatin followed by cisplatin and radiation (Arm 1) and nab-paclitaxel followed by cetuximab and radiation (Arm 2) for locally advanced head and neck squamous-cell carcinoma: a multicenter, non-randomized phase 2 trial.

In locally advanced head and neck squamous-cell carcinoma (LA-HNSCC), clinical complete response (cCR) at the primary site, assessed by clinical examination, after induction chemotherapy predicts for a low relapse risk after subsequent chemoradiotherapy. Prior studies showed a cCR rate of 77% with induction nanoparticle albumin-bound (nab)-paclitaxel given with cisplatin and 5-fluorouracil (APF). The primary aims of this non-randomized phase 2 trial were to determine the cCR rate after induction nab-paclitaxel and cisplatin (Arm 1) and after nab-paclitaxel monotherapy (Arm 2). Eligibility required LA-HNSCC, T2-T4 stage classification, and suitable (Arm 1) or unsuitable (Arm 2) candidates for cisplatin. Arm 1 patients received nab-paclitaxel and cisplatin, then cisplatin with radiation. Arm 2 patients received nab-paclitaxel, then cetuximab with radiation. The primary endpoint was cCR after two cycles of induction chemotherapy. Each arm enrolled forty patients. cCR at the primary site occurred in 28 patients (70%) after nab-paclitaxel and cisplatin and in 8 patients (20%) after nab-paclitaxel monotherapy. The overall clinical response rate was 98% after nab-paclitaxel and cisplatin and 90% after nab-paclitaxel monotherapy. In subset analyses, cCR rates by T stage classifications (T2, T3, T4) were 54, 86, and 69% after nab-paclitaxel and cisplatin, and 14, 11, and 26% after nab-paclitaxel. cCR rates by human papillomavirus status (p16 positive oropharynx vs other) were 72 and 64% after nab-paclitaxel and cisplatin and 35 and 9% after nab-paclitaxel. The cCR rate after nab-paclitaxel and cisplatin was similar to APF; however, the cCR rate after nab-paclitaxel monotherapy was lower. The trial was registered at ClinicalTrials.gov NCT02573493 on October 9, 2015.

Reliance on Self-Medication Increase Delays in Diagnosis and Management of GI Cancers: Results From Nepal.

PURPOSE: Patients with GI cancers in Nepal often present with advanced disease and poor outcomes. The purpose of the study was to determine the time to presentation, diagnosis, and treatment of GI cancer and the baseline factors that may be associated with delays. PATIENTS AND METHODS: An institutional review board-approved study was performed in Kathmandu, Nepal, from July 2018 to June 2019. Patients with newly diagnosed GI cancers were asked to fill out a standardized questionnaire. Baseline factors such as residence, literacy, and use of self-medication were recorded. Patients were asked to report the time from first symptom to presentation, time from primary care visit to pathologic diagnosis, and time from diagnosis to surgery and/or treatment. Baseline factors were analyzed using 2-tailed t tests (Prism 8.0; GraphPad, La Jolla, CA) to determine whether any factors were associated with longer time delays in these 3 intervals. RESULTS: The cohort comprised of 104 patients with a median age of 53.5 years (range, 22-77 years); 61.5% were men, 46.2% had upper GI cancers, and 83.7% presented with stage III or IV disease. The median time to presentation was 150 days, time to diagnosis was 220 days, and time to treatment was 50 days. There was no statistically significant difference in time intervals between upper and lower GI cancers. Use of self-medication (88.5%) was the only factor associated with longer time intervals to presentation, diagnosis, and treatment. CONCLUSION: Patients in Nepal have long time intervals to presentation, diagnosis, and treatment of GI cancer. Self-medication led to longer delays. Reasons for self-medication and other potential barriers will be explored in future studies in the hopes of improving outcomes.

Randomized Phase II Trial to Compare the Efficacy of Haloperidol and Olanzapine in the Control of Chemotherapy-Induced Nausea and Vomiting in Nepal.

PURPOSE: The purpose of the study was to compare efficacy and toxicity of olanzapine (OLN; a higher-cost drug) and haloperidol (HAL; a lower-cost drug) in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who receive highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: In a randomized, phase II trial, patients were randomly assigned to receive either OLN 10 mg orally on days 1 to 4 or HAL 1 mg orally on day 1 and 0.5 mg twice daily on days 2 to 4. Both groups received ondansetron 16 mg and dexamethasone 12 mg intravenously on day 1. Patients recorded their nausea using the Edmonton Symptom Assessment Scale (ESAS) and recorded daily episodes of vomiting from day 1 to day 5. The primary end point was complete nausea prevention (CNP; ie, ESAS of 0). Secondary end point was complete emesis prevention (CEP). RESULTS: Sixty-five patients were randomly assigned, and 64 received their allocated treatment (n = 32 in each arm). There was no difference in CNP during the overall period (days 1 to 5) between OLN and HAL (68.7% v 71.8%; P = .78). In the acute period (day 1) and the delayed period (days 2 to 5), CNP was similar between OLN and HAL (acute: 84.3% v 81.2%; delayed: 68.7% v 75%). No difference was identified in the rate of CEP during the overall period (81.2% with OLN v 78.1% with HAL; P = .75), during the acute period (93.7% with OLN v 90.6% with HAL), or during the delayed period (84.3% with OLN v 84.3% with HAL). No difference in toxicities was noted between treatment arms. CONCLUSION: In this study, HAL had comparable efficacy to OLN in the management of CINV, which suggests that it is the higher-value option in patients who receive HEC in resource-scarce countries.